Cancer is the second leading cause of human death next to coronary disease. Worldwide, millions of people die from cancer every year. In the United States alone, as reported by the American Cancer Society, cancer causes the death of well over a half-million people annually, with over 1.2 million new cases diagnosed per year. While deaths from heart disease have been declining significantly, those resulting from cancer generally are on the rise. In the early part of the next century, cancer is predicted to become the leading cause of death.
Worldwide, several cancers stand out as the leading killers. With very few exceptions, metastatic disease from a carcinoma is fatal. Moreover, even for those cancer patients who initially survive their primary cancers, common experience has shown that their lives are dramatically altered. Many cancer patients experience strong anxieties driven by the awareness of the potential for recurrence or treatment failure. Many cancer patients experience physical debilitations following treatment. Furthermore, many cancer patients experience a recurrence.
While previously identified markers such as PSA, PSM, PCTA and 161P2F10B have facilitated efforts to diagnose and treat prostate cancer, there is need for the identification of additional markers and therapeutic targets for prostate and related cancers in order to further improve diagnosis and therapy.
Renal Cell Cancer (RCC) presently ranks 10th as the leading cause of cancer death in the United States. An estimated 51,190 people will be diagnosed annually with renal cell carcinoma in the US and approximately 12,890 died from the disease in 2007 (American Cancer Society). Historically, treatment has focused primarily on nephrectomy, followed by nonspecific immunotherapy, and sometimes radiation therapy (Hauke, 2006). Nonspecific immunotherapy includes treatment with the cytokines interleukin-2 or interferon-α as either single agents or in combination. After surgical excision, 20-30% of patients will develop metastatic disease within 1-3 years, often in the lung (Motzer, et al., 2006). Median survival for patients with metastatic disease is approximately 13 months (Cohen and McGovern, 2005).
Since 2005, six (6) agents have been approved by FDA for the treatment advanced renal cell cancer. These advances include several agents that target the specific pathways implicated in renal cell cancer. These agents include sorafenib (Nexavar®, FDA approved in December 2005), sunitinib (Sutent®, FDA approved in January 2006), temsirolimus (Torisel®, FDA approved in May 2007), everolimus (Affinitor®, FDA approved in March, 2009), bevacizumab (Avastin® in combination with interferon alpha, FDA approved in August 2009) and pazopanib (Votrient® FDA approved in October 2009). However, despite advances in the treatment, metastatic Renal cell cancer remains incurable and only temsirolimus was approved based on an advantage in overall survival.
Additionally, hepatocellular carcinoma (i.e., cancer of the liver) accounts for 80-90% of all liver cancers. This type of liver cancer occurs more often in men than in women. It is usually seen in people ages 50-60. Generally, treatment of liver cancer is aggressive surgery or a liver transplant which may successfully treat small or slow growing tumors if they are diagnosed early. However, few patients are diagnosed early. Chemotherapy and radiation treatments are not usually effective. However, these therapies are used to shrink tumors so surgery has a greater chance of success. Sorafenib tosylate (Nexavar®) is now available for patients with liver cancer. The prognosis for patients with liver cancer is usually poor, since only 10-20% of hepatocellular carcinomas can be removed using surgery. Accordingly, there is a need to develop an agent used to treat liver cancer.
The therapeutic utility of monoclonal antibodies (mAbs) (G. Kohler and C. Milstein, Nature 256:495-497 (1975)) is being realized. Monoclonal antibodies have now been approved as therapies in transplantation, cancer, infectious disease, cardiovascular disease and inflammation. Different isotypes have different effector functions. Such differences in function are reflected in distinct 3-dimensional structures for the various immunoglobulin isotypes (P. M. Alzari, et al., Annual Rev. Immunol., 6:555-580 (1988)).
Because mice are convenient for immunization and recognize most human antigens as foreign, mAbs against human targets with therapeutic potential have typically been of murine origin. However, murine mAbs have inherent disadvantages as human therapeutics. They require more frequent dosing as mAbs have a shorter circulating half-life in humans than human antibodies. More critically, the repeated administration of murine antibodies to the human immune system causes the human immune system to respond by recognizing the mouse protein as a foreign and generating a human anti-mouse antibody (HAMA) response. Such a HAMA response may result in allergic reaction and the rapid clearing of the murine antibody from the system thereby rendering the treatment by murine antibody useless. To avoid such affects, attempts to create human immune systems within mice have been attempted.
Initial attempts hoped to create transgenic mice capable of responding to antigens with antibodies having human sequences (See Bruggemann, et al., Proc. Nat'l. Acad. Sci. USA 86:6709-6713 (1989)), but were limited by the amount of DNA that could be stably maintained by available cloning vehicles. The use of yeast artificial chromosome (YAC) cloning vectors led the way to introducing large germline fragments of human Ig locus into transgenic mammals. Essentially a majority of the human V, D, and J region genes arranged with the same spacing found in the human genome and the human constant regions were introduced into mice using YACs. One such transgenic mouse strain is known as XenoMouse® mice and is commercially available from Amgen Fremont, Inc. (Fremont Calif.).